Death rates due to heart failure continue to rise steadily in the western world despite better strategies designed to salvage damaged or dying myocardium after myocardial infarction. In the United States alone, it is estimated that 5 million people have congestive heart failure presently and 500,000 more are diagnosed each year. The most prominent cause of myocardial infarction (MI) and subsequent myocardial cell death is undiagnosed coronary artery disease resulting in plaque rupture or dislodgement and myocardial cell ischemia. After an MI, myocardial cells that die or are damaged are replaced by collagen and fibroblasts in a healing process that remodels the heart, most typically the left ventricle. This tissue is non-functioning scar tissue and often leads to a permanent decrease in the efficiency of the myocardium.
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Cellular cardiomyoplasty, or cell-based cardiac repair, is a new potential therapeutic modality in which progenitor cells are used to repair regions of damaged or necrotic myocardium. The ability of transplanted progenitor cells to improve function within the failing heart has been shown in experimental animal models and in some human clinical trials. In November 2011, a large group of collaborators at Minneapolis Heart Institute Foundation at Abbott Northwestern found no significant difference in left ventricular ejection fraction (LVEF) or other markers, between a group of patients treated with cellular cardiomyoplasty and a group of control patients. In this study, all patients were post MI, post percutaneous coronary intervention (PCI) and that infusion of progenitor cells occurred 2–3 weeks after intervention. In a study that is currently underway (February 2012), however, more positive results were being reported: In the SCIPIO trial, patients treated with autologous cardiac stem cells post MI have been reported to be showing statistically significant increases in LVEF and reduction in infarct size over the control group at four months after implant. Positive results at the one-year mark are even more pronounced. Yet the SCIPIO trial "was recently called into question". Harvard University is "now investigating the integrity of some of the data". The Lancet recently published an non-specific ‘Expression of concern’ about the paper. Subsequently another preclinical study also raised doubts on the rational behind using this special kind of cells, as it was found that the special cells only have a minimal ability in generating new cardiomyocytes. Some specialists therefore now raise concerns to continue.
Progenitor cell lines
To date, the ideal progenitor cells have not been found or created. With the goal of recreating human tissue, the use of embryonic stem cells (ESC) was the initial logical choice. These pluripotent cells can conceptually give rise to any somatic cell line in the human body and while animal studies have shown restoration of cardiac function, immunologic rejection issues and teratoma formation have rendered ESC's a high risk.
Human-induced pluripotent stem cells (iPSCs) are a cell line derived from somatic cells which have been induced through a combination of transcription factors. The iPSC line is very similar or identical to ESCs in many regards and also shows great promise in cardiac potential. This cell line, however, is also less than ideal in that this cell type has been unable to mature into a homogeneous cell culture, making it immunogenic and teratogenic. To date, neither of the above cell lines has been involved in a clinical trial for the issues mentioned.
A third cell line that shows great promise and has no known safety concerns is the adult stem cell derived from bone marrow or from cardiac tissue explants. It has been shown in several studies that adult stem cells do have cardiogenic potential. Additionally, adult stem cells derived from bone marrow and cardiac harvest are safe and have never been implicated in immune or oncogenic episodes. The downsides to utilizing adult stem cells are limited proliferation, low quantities, low survival, low persistence and commitment. The bottom line is that these cells have been stressed and aged unlike ESCs and iPSCs but the upside is the lack of all deleterious effects of the younger cell lines. Progenitor cells derived from cardiac tissue explants are being utilized in the SCIPIO trial discussed in the "Overview" section (ClinicalTrials.gov identifier NCT00474461).
Future direction
Presently, the success of adult stem cells in regenerating human myocardium is just a fraction of what it could be. Three major challenges have been observed. Adult stem cells exhibit a minimal commitment to engraft into the damaged myocardium, they have low survival rates and they have limited proliferation. The positive effects observed in clinical trials today are a result of the work of donated stem cells that persist in the damaged myocardium for just days to weeks after delivery. Clearly, if cell survival is prolonged, these effects could be greatly enhanced. This is where a majority of research is being done today and several methodologies hold great promise.
It has been shown that survival rates can be extended by conditioning stem cells with pre-treatments such as cytokines, growth factors, anti-aging compounds and exposure to hypoxic (low oxygen) conditions prior to delivery into host tissue. Genetic modifications which lend endurance and longevity to stem cells placed in damaged myocardium are being investigated as well. Modification by integrated or episomal DNA has been shown to potentiate longevity in stem cells with such factors as GSK3-β, GATA4, Bcl-2, and HSP-20.
Adult stem cell commitment is required for the production of new myocytes, blood vessels and endothelium after donation. While there are methods to induce cellular differentiation utilized with success in other tissue, there has been limited success with myocardial tissue. One of the most promising new techniques has to do with manipulating cells with Notch, a network regulator of commitment and survival that has been very effective in myocardial tissue. There is more work to be done but it seems likely that Notch may be an effective enhancer of stem cell commitment and longevity.
As the field of regenerative medicine grows during its second decade of intense research, there is an international quest for greater understanding. Much is being learned quickly and it will only be a matter of time before new successes lead to real clinical advances in the growing patient population with myocardial compromise.